(1) Field of the Invention
The present invention relates to a method for the treatment of a mammal with viral induced hepatitis by administering a thymosin to the mammal over a period of time to produce regression of the disease. In particular, the present invention relates to the treatment of type B virus chronic hepatitis.
(2) Prior Art
Chronic type B hepatitis, a common form of chronic liver disease, is associated with increased risk for development of cirrhosis, hepatic failure and hepatocellular carcinoma (Seeff, L. B., et al., Sem Liver Dis 6:11-22 (1986)). Impaired effectiveness of the host cellular immune mechanisms in clearing hepatitis B virus (HBV) infected hepatocytes has been proposed to explain development of chronic HBV infection (Thomas, H. C., et al. Sem Liver Dis 6:34-41 (1986)). Antiviral agents have been employed in efforts to treat this disease, among which alpha-interferon (IFN-alpha) has emerged to date as the most efficacious (Hoofnagle J. H., et al., Gastroenterology 95:1318-1325 (1988); and Perillo, R. P., et al., Ann Int Med 109:95-100 (1988)). Unfortunately, IFN-alpha can cause significant side effects requiring cessation of therapy (Hoofnagle J. H., et al., Gastroenterology 95:1318-1325 (1988); Perillo, R. P., et al., Ann Int Med 109:95-100 (1988); and Renault, P. F., et al., Sem Liver Dis 9:273-277 (1989)).
Clinical trials utilizing immune modifiers in the treatment of chronic HBV, such as interleukin 2 (IL2) and levamisole have been inconclusive or have resulted in ineffective responses (Kakumu, S., et al. Hepatology, 8:487-492 (1988); Fattovich, G., et al., Gastroenterology 91:692-696 (1986)).
Thymic extracts or thymus derived peptides, which are chemically different from the thymosins, have been used in clinical trials in the treatment of chronic hepatitis B. In one study (Romeo, F., et al., Arzheim-Forsch/Drug Res. 37:450-456 (1987)), thymostimulin, an extract of calf thymus, resulted in clinical, biochemical and histological improvement; however, treatment effect on HBV markers was not reported. Similar responses have been reported in other studies using thymopeptide (Zhang, D-F, et al., Chinese Med. J. 99:791-798 (1986)) and thymic factor `x` (Dabrowski, M. P., et al., Clin. Immunol. Immunopathol. 16:297-307 (1980)). TF5 is a partially purified extract of bovine thymus containing at least 40 peptide components, 20 of which have been purified to homogeneity or near homogeneity (Low, T. L. K., et al., Thymus 6:27-42 (1984)). Several of these peptides, including T-alpha.sub.1, have been sequenced and chemically synthesized (Wetzel, R., et al., Biochem 19:6096-6104 (1980); and Low, T. L. K., et al., J. Biol. Chem. 254:981-986 (1979)).
In previous studies, thymosin fraction 5 was shown, in vitro, to decrease spontaneous cell mediated cytotoxicity in patients with CAHB (Mutchnick, M. G., et al., Clin. Immunol. Immunopathol. 16:423-437 (1980)) and to enhance Con A induced suppressor cell function in PBM from these patients (Mutchnick, M. G., et al., Dig. Dis Sci 28:328-334 (1983)).
Thymosin fraction 5 (TF5) and thymosin alpha.sub.1 (T-alpha.sub.1), have been shown to trigger maturational events in lymphocytes, augment T cell function and promote reconstitution of immune defects (Low, T. L. K., et al., Thymus 6:27-42 (1984)). These compositions are thus immunomodulators.
TF5 and T-alpha.sub.1 are potent inducers of T cells and can influence immunoregulatory T cell function (Low, T. L. K., et al., Thymus 6:27-42 (1984); Low, T. L. K., et al., J. Biol. Chem. 254:981-986 (1979); Marshall, G. D., et al., J. Immunol, 126:741-744 (1981); and Mutchnick, M. G., et al., Clin. Immunol. Immunopathol. 23:626-633 (1982)). TF5 and T-alpha.sub.1 have been shown to enhance T4 cell function, promote IFN-alpha, IFN-.gamma. and IL2 production by human lymphocytes, and to increase lymphocyte IL2 receptor expression (Low, T. L. K., et al., Thymus 6:27-42 (1984); Sztein, M. B, et al., Proc Natl Acad Sci USA 83:6107-6111 (1986); Serrate, S. A., et al. J. Immunol. 139:2338-2343 (1987); Baxevanis, C. N., et al., Immunopharm. 13:133-141 (1987); and Svedersky, L. P., et al., Eur. J. Immunol. 12:244-247 (1982)).
Clinical trials of TF5 and T-alpha.sub.1 as primary or adjunctive therapy in patients with immunodeficiency or cancer indicate that these agents enhance immune responsiveness and augment specific lymphocyte functions (Sztein, M. B., et al., Springer Semin Immunopathol. 9:1-18 (1986)). Moreover, these thymic peptides appear to reconstitute immune defects rather than non-specifically augment relatively normal immune parameters. These compositions have not been used to treat HBV.